Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• the present invention relates to a heterocyclic compound or a salt thereof useful as an anti-HIV agent.
• HIV human immunodeficiency virus
• AIDS acquired immune deficiency syndrome
• proviral DNA is integrated into the DNA of the target cell by HIV-specific integrase.
• the proviral DNA incorporated into the target cell is transcribed into an RNA strand and efficiently produces viral proteins by viral regulatory gene products such as Tat and Rev.
• Viral proteins bud from the host cell membrane surface in combination with separately formed viral RNA.
• Viruses that have migrated out of the cell repeatedly infect and proliferate immune-responsive cells (such as CD4-positive T cells and macrophages), resulting in immunodeficiency in the host. Many anti-HIV agents have been developed so far.
• nucleic acid-based reverse transcriptase inhibitors zidovudine, didanosine, lamivudine, sanylvudine, abacavir, tenofovir and emtricitabine, non-nucleic acid reverse transcriptase inhibitors nevirapine, delavirdine, Efavirenz and etavirin, protease inhibitors indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, atazanavir, fosamprenavir, tipranavir and darunavir, integrase inhibitor raltegravir, fusion inhibitor enfuvirtide.
• Non-patent Document 1 a combination of any one of a non-nucleic acid reverse transcriptase inhibitor, a protease inhibitor or an integrase inhibitor and two nucleic acid reverse transcriptase inhibitors is recommended.
• Non-patent Document 2 a combination of any one of a non-nucleic acid reverse transcriptase inhibitor, a protease inhibitor or an integrase inhibitor and two nucleic acid reverse transcriptase inhibitors.
• Non-patent Document 2 a combination of any one of a non-nucleic acid reverse transcriptase inhibitor, a protease inhibitor or an integrase inhibitor and two nucleic acid reverse transcriptase inhibitors.
• Non-Patent Documents 3 and 4 As side effects of currently used drugs, for example, complications such as lactic acidosis caused by nucleic acid-based reverse transcriptase inhibitors, lipid metabolism abnormalities caused by protease inhibitors, and diabetes have been reported (Non-Patent Documents 3 and 4). ).
• a compound having an excellent anti-HIV activity is strongly desired.
• R 1 and R 2 are the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, an optionally substituted C 1-12 alkyl group, or an optionally substituted C 2- 12 alkenyl group, optionally substituted C 2-12 alkynyl group, optionally substituted C 1-6 alkoxy group, optionally substituted acyl group, optionally substituted C 1-6 alkyl
• R 3 represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, an optionally substituted C 1-6 alkyl group, optionally substituted C 1-6 alkoxy group, an amino group, which may be protected A good carboxyl group or an optionally protected hydroxyl group;
• Z is a nitrogen atom or a general formula CR 6 wherein R 6 is a hydrogen atom, a halogen atom, a cyano group, a nitro group, an optionally substituted C 1-12 alkyl group or an optionally substituted C A 2-12 alkenyl group, an optionally substituted C 2-12 alkynyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted acyl group, an optionally substituted C 1-1 6 alkylamino group, optionally substituted di (C 1-6 alkyl) amino group, optionally substituted C 1-6 alkylthio group, optionally substituted C 1-6 alkylsulfon
• the heterocyclic compound of the present invention or a salt thereof has excellent anti-HIV activity, it is useful as an anti-HIV agent.
• the heterocyclic compound of the present invention or a salt thereof is excellent in safety and kinetics and is useful as an anti-HIV agent.
• Halogen atom means fluorine atom, chlorine atom, bromine atom or iodine atom.
• the C 1-12 alkyl group is a straight chain or branched chain such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl and octyl groups.
• the C 1-6 alkyl group means a linear or branched C 1-6 such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl and hexyl groups.
• An alkyl group is meant.
• the C 2-12 alkenyl group vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, 1,3-butadienyl, pentenyl, hexenyl, of heptenyl and linear, such as octenyl or branched C 2-
• the C 2-6 alkenyl group means a linear or branched C 2-6 alkenyl group such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, 1,3-butadienyl, pentenyl and hexenyl groups. means.
• the C 2-12 alkynyl group means a linear or branched C 2-12 alkynyl group such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl and octynyl groups.
• C 3-8 cycloalkyl group means a C 3-8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
• An aryl group means a phenyl, naphthyl, indanyl, indenyl or tetrahydronaphthyl group.
• An ar C 1-6 alkyl group means an ar C 1-6 alkyl group such as benzyl, diphenylmethyl, trityl, phenethyl and naphthylmethyl groups.
• the C 1-6 alkylene group means a linear or branched C 1-6 alkylene group such as methylene, ethylene, propylene, butylene and hexylene groups.
• the C 2-6 alkenylene group means a linear or branched C 2-6 alkenylene group such as vinylene, propenylene, butenylene and pentenylene groups.
• the C 2-6 alkynylene group means a linear or branched C 2-6 alkynylene group such as ethynylene, propynylene, butynylene and pentynylene groups.
• the C 1-6 alkoxy group means a linear or branched C 1 -1 group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy groups.
• 6 means an alkyloxy group.
• An aryloxy group means a phenoxy or naphthyloxy group.
• the C 1-6 alkoxy C 1-6 alkyl group means a C 1-6 alkyloxy C 1-6 alkyl group such as methoxymethyl and 1-ethoxyethyl group.
• Al C 1-6 alkoxy C 1-6 alkyl group means an al C 1-6 alkyloxy C 1-6 alkyl group such as benzyloxymethyl and phenethyloxymethyl groups.
• the C 2-12 alkanoyl group means a linear or branched C 2-12 alkanoyl group such as acetyl, propionyl, valeryl, isovaleryl and pivaloyl groups.
• An aroyl group means a benzoyl or naphthoyl group.
• the heterocyclic carbonyl group means nicotinoyl, thenoyl, pyrrolidinocarbonyl or furoyl group.
• the ( ⁇ -substituted) aminoacetyl group is an amino acid (glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, arginine, lysine, histidine, hydroxylysine, phenylalanine. , Tyrosine, tryptophan, proline and hydroxyproline, etc.) means the N-terminus derived from ( ⁇ -substituted) aminoacetyl group which may be protected.
• amino acid glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, arginine, lysine, histidine, hydroxylysine, phenylalanine. , Tyrosine, try
• An acyl group means a formyl group, a succinyl group, a glutaryl group, a maleoyl group, a phthaloyl group, a C 2-12 alkanoyl group, an aroyl group, a heterocyclic carbonyl group, an ( ⁇ -substituted) aminoacetyl group, or the like.
• An acyl C 1-6 alkyl group means an acyl C 1-6 alkyl group such as acetylmethyl, benzoylmethyl and 1-benzoylethyl groups.
• acyloxy C 1-6 alkyl group means acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, a benzoyloxy methyl and 1- acyloxy C 1-6 alkyl group such as (benzoyloxy) ethyl.
• the C 1-6 alkoxycarbonyl group is a linear or branched C 1-6 alkyloxy group such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, and 1,1-dimethylpropoxycarbonyl group. Means a carbonyl group.
• the al C 1-6 alkoxycarbonyl group means an al C 1-6 alkyloxycarbonyl group such as benzyloxycarbonyl and phenethyloxycarbonyl groups.
• An aryloxycarbonyl group means a phenyloxycarbonyl or naphthyloxycarbonyl group.
• the C 1-6 alkylamino group is a linear or branched chain such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, tert-butylamino, pentylamino and hexylamino groups.
• -Like C 1-6 alkylamino group is a linear or branched chain such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, tert-butylamino, pentylamino and hexylamino groups.
• Di (C 1-6 alkyl) amino group means dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, di (tert-butyl) amino, dipentylamino, dihexylamino, (ethyl) (methyl) amino and A linear or branched di (C 1-6 alkyl) amino group such as a (methyl) (propyl) amino group is meant.
• the C 1-6 alkylthio group means a C 1-6 alkylthio group such as methylthio, ethylthio and propylthio groups.
• the C 1-6 alkylsulfonyl group means a C 1-6 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl and propylsulfonyl groups.
• the arylsulfonyl group means benzenesulfonyl, p-toluenesulfonyl or naphthalenesulfonyl group.
• the C 1-6 alkylsulfonyloxy group means a C 1-6 alkylsulfonyloxy group such as methylsulfonyloxy and ethylsulfonyloxy groups.
• the arylsulfonyloxy group means benzenesulfonyloxy or p-toluenesulfonyloxy group.
• a silyl group means a trimethylsilyl, triethylsilyl, or tributylsilyl group.
• Monocyclic nitrogen-containing heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, piperidyl, tetrahydropyridyl, pyridyl, homopiperidinyl, octahydroazosinyl, imidazolidinyl, imidazolinyl, imidazolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, piperazinyl, pyrazylyl
• a monocyclic nitrogen-containing heterocyclic group containing only a nitrogen atom as a hetero atom forming the ring such as pyridazinyl, pyrimidinyl, homopiperazinyl, triazolyl and tetrazolyl groups.
• the monocyclic oxygen-containing heterocyclic group means a tetrahydrofuranyl, furanyl, tetrahydropyranyl or pyranyl group.
• the monocyclic sulfur-containing heterocyclic group means a thienyl group and the like.
• the monocyclic nitrogen-containing / oxygen heterocyclic group is a monocyclic nitrogen-containing / oxygen heterocyclic ring containing only a nitrogen atom and an oxygen atom as hetero atoms forming the ring, such as oxazolyl, isoxazolyl, oxadiazolyl and morpholinyl groups. Means a formula group.
• a monocyclic nitrogen-containing / sulfur heterocyclic group is a heterocycle that forms the ring such as thiazolyl, isothiazolyl, thiadiazolyl, thiomorpholinyl, 1-oxidethiomorpholinyl and 1,1-dioxidethiomorpholinyl groups.
• a monocyclic nitrogen-containing / sulfur heterocyclic group containing only nitrogen and sulfur atoms as atoms.
• Monocyclic heterocyclic group means monocyclic nitrogen-containing heterocyclic group, monocyclic oxygen-containing heterocyclic group, monocyclic sulfur-containing heterocyclic group, monocyclic nitrogen-containing / oxygen heterocyclic group It means a group or a monocyclic nitrogen-containing / sulfur heterocyclic group.
• Bicyclic nitrogen-containing heterocyclic group includes indolinyl, indolyl, isoindolinyl, isoindolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, tetrahydroquinolinyl, quinolyl, tetrahydroisoquinolinyl, isoquinolinyl, quinolidinyl, Means a bicyclic nitrogen-containing heterocyclic group containing only a nitrogen atom as a hetero atom forming the ring, such as cinnolinyl, phthalazinyl, quinazolinyl, dihydroquinoxalinyl, quinoxalinyl, naphthyridinyl, purinyl, pteridinyl and quinuclidinyl groups To do.
• Bicyclic oxygen-containing heterocyclic groups are 2,3-dihydrobenzofuranyl, benzofuranyl, isobenzofuranyl, chromanyl, chromenyl, isochromanyl, 1,3-benzodioxolyl, 1,3-benzodi It means a bicyclic oxygen-containing heterocyclic group containing only an oxygen atom as a hetero atom forming the ring, such as oxanyl and 1,4-benzodioxanyl group.
• the bicyclic sulfur-containing heterocyclic group is a bicyclic sulfur-containing heterocyclic group containing only a sulfur atom as a hetero atom forming the ring, such as 2,3-dihydrobenzothienyl and benzothienyl groups. Means.
• Bicyclic nitrogen-containing / oxygen heterocyclic groups include benzoxazolyl, benzisoxazolyl, benzooxadiazolyl, benzomorpholinyl, dihydropyranopyridyl, dihydrodioxynopyridyl and dihydropyridoxoxa It means a bicyclic nitrogen-containing / oxygen heterocyclic group containing only nitrogen and oxygen atoms as the hetero atoms forming the ring, such as a dinyl group.
• Bicyclic nitrogen-containing / sulfur heterocyclic groups include bicyclic inclusions containing nitrogen and sulfur atoms as the hetero atoms forming the ring, such as benzothiazolyl, benzisothiazolyl and benzothiadiazolyl groups. Nitrogen / sulfur heterocyclic group.
• a bicyclic heterocyclic group is a bicyclic nitrogen-containing heterocyclic group, a bicyclic oxygen-containing heterocyclic group, a bicyclic sulfur-containing heterocyclic group, or a bicyclic nitrogen-containing group. -An oxygen heterocyclic group or a bicyclic nitrogen-containing / sulfur heterocyclic group.
• the heterocyclic group means a monocyclic heterocyclic group or a bicyclic heterocyclic group.
• Examples of the leaving group include a halogen atom, a C 1-6 alkylsulfonyloxy group, and an arylsulfonyloxy group.
• the C 1-6 alkylsulfonyloxy group or arylsulfonyloxy group may have a substituent.
• Amino protecting groups include all groups that can be used as protecting groups for ordinary amino groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pages 696-926, 2007, John Wiley & Sons (John Wiley & Sons, INC.) And the like. Specifically, an al C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, an acyl group, a C 1-6 alkoxycarbonyl group, an al C 1-6 alkoxycarbonyl group, an aryloxycarbonyl group, Examples thereof include a C 1-6 alkylsulfonyl group, an arylsulfonyl group, and a silyl group.
• Examples of the imino protecting group include all groups that can be used as protecting groups for ordinary imino groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pages 696-868, 2007, John Wiley & Sons (John Wiley & Sons, INC.) And the like. Specifically, an al C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, an acyl group, a C 1-6 alkoxycarbonyl group, an al C 1-6 alkoxycarbonyl group, an aryloxycarbonyl group, Examples thereof include a C 1-6 alkylsulfonyl group, an arylsulfonyl group, and a silyl group.
• Hydroxyl protecting groups include all groups that can be used as protecting groups for normal hydroxyl groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pages 16-299, 2007, John Wiley & Sons (John Wiley & Sons, INC.) And the like.
• a C 1-6 alkyl group a C 2-6 alkenyl group, an al C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, an al C 1-6 alkoxy C 1-6 alkyl Group, acyl group, C 1-6 alkoxycarbonyl group, al C 1-6 alkoxycarbonyl group, C 1-6 alkylsulfonyl group, arylsulfonyl group, silyl group, tetrahydrofuranyl group or tetrahydropyranyl group.
• the carboxyl protecting group includes all groups that can be used as protecting groups for ordinary carboxyl groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 533-643, 2007, John Wiley & Sons (John Wiley & Sons, INC.) And the like. Specifically, C 1-6 alkyl group, C 2-6 alkenyl group, aryl group, al C 1-6 alkyl group, C 1-6 alkoxy C 1-6 alkyl group, al C 1-6 alkoxy C 1 Examples include a -6 alkyl group, an acyl C 1-6 alkyl group, an acyloxy C 1-6 alkyl group, and a silyl group.
• Examples of the aliphatic hydrocarbons include pentane, hexane, and cyclohexane.
• Examples of halogenated hydrocarbons include methylene chloride, chloroform or dichloroethane.
• Examples of alcohols include methanol, ethanol, propanol, 2-propanol, butanol or 2-methyl-2-propanol.
• Examples of ethers include diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and diethylene glycol diethyl ether.
• ketones include acetone, 2-butanone and 4-methyl-2-pentanone.
• esters include methyl acetate, ethyl acetate, propyl acetate, and butyl acetate.
• amides include N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone.
• Aromatic hydrocarbons include benzene, toluene or xylene.
• Examples of the sulfoxides include dimethyl sulfoxide.
• Examples of nitriles include acetonitrile.
• Examples of the salt of the compound represented by the general formula [1] include a conventionally known salt in a basic group such as an amino group or an acidic group such as a hydroxyl group or a carboxyl group.
• Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, Salts with organic carboxylic acids such as tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.
• salts in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine And a salt thereof.
• preferred salts include pharmacologically acceptable salts.
• C 1-12 alkyl group, C 2-12 alkenyl group, C 2-12 alkynyl group, C 1-6 alkoxy group, acyl group, C 1-6 alkylamino group of R 1 , R 2 and R 6 , di ( C 1-6 alkyl) amino group, C 1-6 alkylthio group and C 1-6 alkylsulfonyl group are each a halogen atom, a cyano group, a nitro group, a C 1-6 alkoxy group, a C 1-6 alkylamino group, a di (C 1-6 alkyl) amino group, C 3-8 cycloalkyl group, aryl group, heterocyclic group, carbamoyl group optionally substituted with C 1-6 alkyl group, amino group optionally protected , An optionally protected carboxyl group, an optionally protected hydroxyl group and an oxo group may be substituted with one or more groups.
• the arylsulfonyl group, C 3-8 cycloalkyl group, aryl group and heterocyclic group of R 1 , R 2 and R 6 are substituted with a halogen atom, a cyano group, a nitro group, a C 1-12 alkyl group or a halogen atom.
• the carbamoyl group of R 1 , R 2 and R 6 is a C 1-12 alkyl group which may be substituted with a halogen atom, a C 2-12 alkenyl group which may be substituted with a halogen atom, or a halogen atom.
• a C 2-12 alkynyl group an acyl group, an ar C 1-6 alkyl group, a C 3-8 cycloalkyl group, an aryl group and a heterocyclic group. Also good.
• the C 1-6 alkyl group and C 1-6 alkoxy group of R 3 are each a halogen atom, a cyano group, a nitro group, a C 1-6 alkoxy group, a carbamoyl group optionally substituted by a C 1-6 alkyl group, It may be substituted with one or more groups selected from an optionally protected amino group, an optionally protected carboxyl group, an optionally protected hydroxyl group and an oxo group.
• the C 3-8 cycloalkyl group, aryl group and heterocyclic group of R 4 and R 7 may be substituted with one or more groups selected from a halogen atom, a cyano group, a nitro group, and substituent group A.
• Substituent group A Halogen atom, C 1-6 alkoxy group, C 1-6 alkylamino group, di (C 1-6 alkyl) amino group, optionally protected amino group, optionally protected carboxyl group, protected May be a hydroxyl group.
• the C 1-6 alkyl group of R 5 and R 8 is a halogen atom, a cyano group, a nitro group, a C 1-6 alkoxy group, a carbamoyl group which may be substituted with a C 1-6 alkyl group, or a protected group. It may be substituted with one or more groups selected from an amino group, an optionally protected carboxyl group, an optionally protected hydroxyl group and an oxo group.
• the C 1-6 alkylene group, C 2-6 alkenylene group and C 2-6 alkynylene group of Y 1 and Y 2 are each a halogen atom, a cyano group, a nitro group, a C 1-6 alkoxy group, an aryl group, a C 1-1
• One or more groups selected from a carbamoyl group optionally substituted with 6 alkyl groups, an amino group which may be protected, a carboxyl group which may be protected, a hydroxyl group which may be protected and an oxo group May be substituted.
• the above groups further include a halogen atom, cyano group, nitro group, C 1-12 alkyl group, C 2-12 alkenyl group, C 2-12 alkynyl group, C 1-6 alkoxy group, acyl group, C 1-6 Alkylamino group, di (C 1-6 alkyl) amino group, C 1-6 alkylthio group, C 1-6 alkylsulfonyl group, arylsulfonyl group, C 3-8 cycloalkyl group, aryl group, heterocyclic group, It may be substituted with one or more groups selected from a carbamoyl group, an amino group, a carboxyl group and a hydroxyl group.
• preferable compounds include the following compounds.
• Z is represented by the general formula CR 6 wherein R 6 is a hydrogen atom, a halogen atom, a cyano group, a nitro group, an optionally substituted C 1-12 alkyl group, or an optionally substituted C 2-12.
• Y 2 represents an optionally substituted C A 1-6 alkylene group, an optionally substituted C 2-6 alkenylene group, an optionally substituted C 2-6 alkynylene group or a bond
• R 7 is an optionally substituted C 3-8 It means a cycloalkyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group. "Means. Are preferred.
• R 1 is represented by the general formula X 1 -Y 1 -R 4 wherein X 1 is the general formula NR 5 wherein R 5 is a hydrogen atom, an optionally substituted C 1-6 alkyl group or Means an imino protecting group ”, an oxygen atom or a sulfur atom; Y 1 is an optionally substituted C 1-6 alkylene group, an optionally substituted C 2-6 alkenylene group, A C 2-6 alkynylene group or a bond; R 4 is an optionally substituted C 3-8 cycloalkyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group Means. Are preferred.
• R 2 and R 6 are the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, an optionally substituted C 1-12 alkyl group, an optionally substituted C 1-6 alkoxy group, Optionally substituted C 1-6 alkylamino group, optionally substituted di (C 1-6 alkyl) amino group, optionally substituted C 1-6 alkylthio group, optionally substituted An aryl group, an optionally substituted heterocyclic group, an optionally substituted carbamoyl group, an optionally protected amino group, an optionally protected carboxyl group or an optionally protected hydroxyl group; Certain compounds are preferred.
• R 2 and R 6 are the same or different and each represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, or a protected group. More preferred are compounds that are optionally amino groups or optionally protected hydroxyl groups.
• R 2 is more preferably a hydrogen atom or an optionally substituted C 1-6 alkyl group, and further preferably an optionally substituted C 1-6 alkyl group. More preferably, R 6 is a hydrogen atom.
• R 3 is a hydrogen atom, a halogen atom, an optionally substituted C 1-12 alkyl group, an optionally substituted C 1-6 alkoxy group or an amino group is preferable.
• R 4 is an optionally substituted aryl group or an optionally substituted heterocyclic group.
• a compound in which X 1 is a general formula NR 5 "wherein R 5 represents a hydrogen atom, an optionally substituted C 1-6 alkyl group or an imino protecting group" is preferred.
• a compound in which Y 1 is an optionally substituted C 1-6 alkylene group or a bond is preferred.
• a compound in which X 1 is NH; and Y 1 is an optionally substituted C 1-6 alkylene group is more preferable.
• a compound in which R 5 is a hydrogen atom is more preferable.
• X 2 is of the general formula NR 8 , wherein R 8 represents a hydrogen atom, an optionally substituted C 1-6 alkyl group or an imino protecting group.
• R 8 represents a hydrogen atom, an optionally substituted C 1-6 alkyl group or an imino protecting group.
• Y 2 is an optionally substituted C 1-6 alkylene group or a bond is preferred.
• a compound in which X 2 is NH; and Y 2 is an optionally substituted C 1-6 alkylene group is more preferable.
• a compound in which R 8 is a hydrogen atom is more preferable.
• R 7 is an optionally substituted aryl group.
• preferable compounds include the following compounds.
• R 1 has the general formula X 1 -Y 1 -R 4 wherein X 1 is NH; Y 1 is an optionally substituted C 1-6 alkylene group; R 4 is substituted Means an optionally substituted aryl group or an optionally substituted heterocyclic group. ”R2; R 2 is a hydrogen atom or an optionally substituted C 1-6 alkyl group; R 3 is a hydrogen atom; A compound in which Z is CH is preferred.
• R 1 has the general formula X 1 -Y 1 -R 4 wherein X 1 is NH; Y 1 is an optionally substituted C 1-6 alkylene group; R 4 is substituted Means an optionally substituted aryl group or an optionally substituted heterocyclic group. ”; R 2 is an optionally substituted C 1-6 alkyl group; R 3 is a hydrogen atom; Z is CH The compound which is is more preferable.
• Examples of preferred compounds in the present invention include 8-hydroxy-4-methyl-5-(((2-methylpyridin-3-yl) methyl) amino) pyrido [2,3-d] pyrimidin-7 (8H) -one, 5-(((5-fluoropyridin-3-yl) methyl) amino) -8-hydroxy-4-methylpyrido [2,3-d] pyrimidin-7 (8H) -one, 8-hydroxy-4-methyl-5-((1- (pyridin-3-yl) ethyl) amino) pyrido [2,3-d] pyrimidin-7 (8H) -one, 8-hydroxy-4-methyl-5-(((2- (morpholin-4-yl) pyridin-3-yl) methyl) amino) pyrido [2,3-d] pyrimidin-7 (8H) -one, 8-hydroxy-4-methyl-5-(((pyridin-3-yl) methyl) amino) pyrido [2,3-d]
• the compound represented by the general formula [1] or a salt thereof exhibits excellent safety and dynamics.
• Safety and kinetics are evaluated by various tests, for example, cytotoxicity test, hERG test, repeated dose toxicity test, cytochrome P450 (CYP) activity inhibition test, metabolism-dependent inhibition test, in vivo mouse
• cytotoxicity test hERG test
• repeated dose toxicity test cytochrome P450 (CYP) activity inhibition test
• metabolism-dependent inhibition test in vivo mouse
• cytotoxicity test for example, cytotoxicity test, hERG test, repeated dose toxicity test, cytochrome P450 (CYP) activity inhibition test, metabolism-dependent inhibition test, in vivo mouse
• CYP cytochrome P450
• the compound of the present invention is produced by combining methods known per se, and can be produced, for example, according to the production method shown below.
• the compound of the general formula [1] can be produced by deprotecting the compound of the general formula [2]. This reaction is described, for example, in Protective Groups ⁇ Organic Synthesis 4th edition, pp. 16-299, 2007, John Wiley & Sons, INC.).
• the compound of the general formula [1] can be produced by reducing the compound of the general formula [2] in the presence of a metal catalyst.
• the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
• Preferable solvents include alcohols and ethers.
• Examples of the metal catalyst used in this reaction include palladium metal such as palladium-carbon and palladium black; palladium salts such as palladium oxide and palladium hydroxide; nickel metal such as Raney nickel; and platinum salts such as platinum oxide. It is done.
• the amount of the metal catalyst used may be 0.001 to 5 times (W / W), preferably 0.01 to 1 times (W / W) of the compound of the general formula [2].
• Examples of the reducing agent include hydrogen; formic acid; formate salts such as sodium formate, ammonium formate and triethylammonium formate; cyclohexene and cyclohexadiene.
• the amount of the reducing agent used may be 2 to 100 times mol, preferably 2 to 10 times mol, of the compound of the general formula [2]. This reaction may be carried out at 0 ° C. to the boiling point of the solvent, preferably 10 to 40 ° C. for 1 minute to 24 hours.
• the compound of the general formula [4] can be obtained by a method known per se, for example, Experimental Chemistry Course 4th Edition, Volume 20, The Chemical Society of Japan. Pp. 279-282 (1992, Maruzen) or a method analogous thereto, can be produced from the corresponding nitrile compound.
• the compound of the general formula [2a] can be produced by reacting the compound of the general formula [3a] with the compound of the general formula [4] in the presence or absence of a base.
• the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
• Preferred solvents include ethers.
• Bases optionally used in this reaction include, for example, inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate, and pyridine, 4- (dimethylamino) pyridine, triethylamine and diisopropylethylamine.
• organic bases such as The amount of the base used may be 1 to 50 times mol, preferably 1 to 2 times mol, of the compound of the general formula [3a].
• the amount of the compound of general formula [4] used may be 1 to 50 times mol, preferably 1 to 2 times mol, of the compound of general formula [3a]. This reaction may be carried out at 0 ° C. to the boiling point of the solvent, preferably at 20 to 120 ° C. for 1 minute to 24 hours.
• the compound of the general formula [2b] can be produced by reacting the compound of the general formula [3b] with the compound of the general formula [4] according to the production method A.
• the compound of the general formula [2c] can be produced by hydrolyzing the compound of the general formula [2b] and then subjecting it to a decarboxylation reaction.
• This reaction is a method known per se, for example, the method described in New Experimental Chemistry Course, Vol. 15, [II], edited by The Chemical Society of Japan, pages 808-811 (1977, Maruzen) or a method analogous thereto. Just do it.
• the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
• Preferable solvents include halogenated hydrocarbons.
• Examples of the base used in this reaction include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate, and pyridine, 4- (dimethylamino) pyridine, triethylamine and diisopropylethylamine.
• inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate
• pyridine 4- (dimethylamino) pyridine
• triethylamine and diisopropylethylamine An organic base is mentioned.
• the amount of the base used may be 1 to 50 times mol, preferably 1 to 2 times mol for the compound of the general formula [7].
• the amount of the compound of the general formula [8] used may be 1 to 50 times mol, preferably 1 to 2 times mol, of the compound of the general formula [7]. This reaction may be performed at ⁇ 20 ° C. to the boiling point of the solvent, preferably ⁇ 10 to 30 ° C. for 1 minute to 24 hours.
• the compound of general formula [10] can be produced by subjecting the compound of general formula [9] to a ring closure reaction in the presence of a base.
• the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
• Preferred solvents include alcohols.
• Examples of the base used in this reaction include metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide; sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate and triphosphate.
• Examples include inorganic bases such as potassium and organic bases such as pyridine, 4- (dimethylamino) pyridine, triethylamine and diisopropylethylamine.
• the amount of the base used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [9]. This reaction may be carried out at 0 ° C. to the boiling point of the solvent, preferably 0 to 30 ° C. for 1 minute to 24 hours.
• the compound of the general formula [3b] can be produced by converting the hydroxyl group of the compound of the general formula [10] into a leaving group.
• L a is, for example, in the case of C 1-6 alkylsulfonyloxy group or an arylsulfonyloxy group, the compound of general formula [3b] in the presence of a base, sulfonyl compounds of general formula [10] chloride compound or sulfonic acid It can be produced by reacting with an anhydride.
• the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
• aliphatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, esters, aromatics examples thereof include hydrocarbons, sulfoxides and nitriles, and these may be used as a mixture.
• Preferable solvents include halogenated hydrocarbons.
• Examples of the base used in this reaction include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate, and pyridine, 4- (dimethylamino) pyridine, triethylamine and diisopropylethylamine.
• inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate
• pyridine 4- (dimethylamino) pyridine
• triethylamine and diisopropylethylamine An organic base is mentioned.
• the amount of the base used may be 1 to 50 times mol, preferably 1 to 2 times mol, of the compound of the general formula [10].
• Examples of the sulfonyl chloride compound used in this reaction include alkanesulfonyl chlorides such as methanesulfonyl chloride and trifluoromethanesulfonyl chloride, and arylsulfonyl chlorides such as benzenesulfonyl chloride and p-toluenesulfonyl chloride.
• Examples of the sulfonic acid anhydride used in this reaction include trifluoromethanesulfonic acid anhydride.
• the amount of the sulfonyl chloride compound or sulfonic anhydride used may be 1 to 50 times mol, preferably 1 to 2 times mol, of the compound of the general formula [10]. This reaction may be carried out at 0 ° C. to the boiling point of the solvent, preferably 0 to 30 ° C. for 1 minute to 24 hours.
• the compound of the general formula [11] can be produced by hydrolyzing the compound of the general formula [10] and then subjecting it to a decarboxylation reaction.
• This reaction is a method known per se, for example, the method described in New Experimental Chemistry Course, Vol. 15, [II], edited by The Chemical Society of Japan, pages 808-811 (1977, Maruzen) or a method analogous thereto. Just do it.
• the compound of the general formula [3c] can be produced by converting the hydroxyl group of the compound of the general formula [11] into a leaving group. This reaction may be carried out by a method known per se or a method analogous thereto, but can be carried out, for example, by a method analogous to production method C-4.
• the compound of the general formula [13] can be produced by reacting the compound of the general formula [7] with the compound of the formula [12] in the presence of a base according to the production method C-2.
• the compound of the general formula [14] can be produced by subjecting the compound of the general formula [13] to a ring-closing reaction in the presence of a base according to the production method C-3.
• the compound of the general formula [3d] can be produced by converting the carbonyl group of the compound of the general formula [14] having tautomerism into a leaving group.
• the compound of the general formula [3d] can be produced by reacting the compound of the general formula [14] with a halogenating agent in the presence of a base.
• the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
• aliphatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, esters, aromatics examples thereof include hydrocarbons, sulfoxides and nitriles, and these may be used as a mixture.
• Preferable solvents include aromatic hydrocarbons.
• Examples of the base used in this reaction include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate, and pyridine, 4- (dimethylamino) pyridine, triethylamine and diisopropylethylamine.
• inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate
• pyridine 4- (dimethylamino) pyridine
• triethylamine and diisopropylethylamine An organic base is mentioned.
• the amount of the base used may be 1 to 50 times mol, preferably 1 to 2 times mol, of the compound of the general formula [14].
• halogenating agent used in this reaction examples include phosphorus pentoxide, phosphorus pentachloride, phosphoryl chloride and thionyl chloride.
• the amount of the halogenating agent used may be 1 to 50 times mol, preferably 1 to 2 times mol, of the compound of the general formula [14].
• a halogenating agent may be used as a solvent. This reaction may be carried out at 0 ° C. to the boiling point of the solvent, preferably 0 to 80 ° C. for 1 minute to 24 hours.
• the compound of the general formula [16] can be produced by reacting the compound of the general formula [7] with the compound of the formula [15] in the presence of a base.
• the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
• Preferable solvents include halogenated hydrocarbons.
• Examples of the base used in this reaction include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate, and pyridine, 4- (dimethylamino) pyridine, triethylamine and diisopropylethylamine.
• inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate
• pyridine 4- (dimethylamino) pyridine
• triethylamine and diisopropylethylamine An organic base is mentioned.
• the amount of the base used may be 1 to 50 times mol, preferably 1 to 2 times mol for the compound of the general formula [7].
• the amount of the compound of the formula [15] used may be 1 to 50 times mol, preferably 1 to 2 times mol, of the compound of the general formula [7]. This reaction may be performed at ⁇ 20 ° C. to the boiling point of the solvent, preferably ⁇ 10 to 30 ° C. for 1 minute to 24 hours.
• the compound of the general formula [14] can be produced by deprotecting the compound of the general formula [16]. This reaction is described, for example, in Protective Groups in Organic Synthesis 4th edition, pages 696-926, 2007, John Wiley & Sons, INC.).
• the compound of the general formula [14] can be produced by reacting the compound of the general formula [16] with a deprotecting agent.
• the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
• Preferred solvents include nitriles and water.
• deprotecting agents used in this reaction include hydrogen; ammonium formate; zinc; sodium; acid chlorides such as vinyl chloroformate and acetyl chloride; organic silanes such as triethylsilane and trimethylsilyl iodide; Hydrides; alkali metal alkoxides such as potassium tert-butoxide; alkali metal thioalkoxides such as sodium thiomethoxide; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; sodium borohydride; potassium fluoride and Alkali metal salts such as sodium iodide; Lewis acids such as boron tribromide, aluminum chloride, ruthenium chloride and zinc chloride; inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; trifluoroacetic acid, methanesulfonic acid and paratoluene Sul Organic acids such as acids; inorganic bases such as potassium carbonate, sodium bi
• the amount of the deprotecting agent used may be 0.01 to 1000 times mol, preferably 0.1 to 100 times mol, of the compound of the general formula [16]. This reaction may be carried out at 0 ° C. to the boiling point of the solvent, preferably 70 to 120 ° C. for 1 minute to 24 hours.
• the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
• Preferable solvents include amides.
• Examples of the base used in this reaction include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate, and pyridine, 4- (dimethylamino) pyridine, triethylamine and diisopropylethylamine.
• inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate
• pyridine 4- (dimethylamino) pyridine, triethylamine and diisopropylethylamine.
• An organic base is mentioned.
• the amount of the base used may be 1 to 50 times mol, preferably 2 to 5 times mol, of the compound of the general formula [5].
• the amount of the compound of general formula [17] used may be 1 to 50 times mol, preferably 2 to 5 times mol, of the compound of general formula [5]. This reaction may be carried out at 0 ° C. to the boiling point of the solvent, preferably 0 to 80 ° C. for 1 minute to 24 hours.
• the compound of the general formula [3e] can be produced by converting the hydroxyl group of the compound of the general formula [18] into a leaving group. This reaction may be carried out by a method known per se or a method analogous thereto, but can be carried out, for example, by a method analogous to production method C-4.
• R d is a hydrogen atom or a hydroxyl protecting group
• L d is a halogen atom
• R 6a is an optionally substituted aryl group, an optionally substituted cycloalkyl group, An optionally substituted heterocyclic group, an optionally substituted C 1-12 alkyl group or an optionally substituted C 2-12 alkenyl group
• R e is a hydrogen atom or an optionally substituted C 1-6 An alkyl group
• R f is an optionally substituted C 1-6 alkylene group
• R 2 , R 3 and R a have the same meanings as described above.
• the compound of the general formula [2e] is prepared according to the method described in, for example, Experimental Chemistry Course 4th Edition, Volume 20, The Chemical Society of Japan, pp. 424-427, 466-467 (1992, Maruzen).
• the compound of the general formula [2d] can be produced by reacting with a halogenating agent.
• the solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction.
• halogenated hydrocarbons; ethers; alcohols; nitriles; dimethyl sulfoxide; Examples include organic acids such as fluoroacetic acid; inorganic acids such as sulfuric acid, and water. These solvents may be used alone or in combination.
• the amount of the solvent to be used is not particularly limited, but is preferably 1 to 200 times the amount (v / w) with respect to the compound of the general formula [2d].
• the halogenating agent used in this reaction is not particularly limited as long as it is a compound usually used in a halogenation reaction of an aromatic compound.
• iodine, bromine, chlorine, sulfuryl chloride, N-iodosuccinimide is used.
• the amount of the halogenating agent used may be 0.05 to 50 times mol, preferably 0.1 to 20 times mol, of the compound of the general formula [2d].
• the additive used as necessary in this reaction is not particularly limited as long as it is a reagent usually used in the halogenation reaction of an aromatic compound.
• a reagent usually used in the halogenation reaction of an aromatic compound Preferably, for example, sodium bromide, lead tetraacetate, titanium chloride is used.
• (IV), aluminum chloride, silver sulfate, trifluoroacetic acid and the like may be mentioned, and these may be used alone or in combination.
• the amount of the additive used in this reaction may be 0.01 to 10 times mol, preferably 0.1 to 10 times mol, of the compound of the general formula [2d].
• This reaction is usually carried out at ⁇ 80 to 170 ° C., preferably ⁇ 80 to 100 ° C. for 1 minute to 72 hours, preferably 5 minutes to 48 hours.
• the compound of the general formula [2f] is obtained by converting the compound of the general formula [2e] into the general formulas [17a] and [17b] in the presence or absence of a base, in the presence of a palladium catalyst, and in the presence or absence of a ligand. Or it can manufacture by making it react with the compound of [17c].
• the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include halogenated hydrocarbons, ethers, alcohols, aromatic hydrocarbons, acetonitrile and water. These solvents may be used as a mixture. Preferred solvents include alcohols, aromatic hydrocarbons and water mixed solvents, and ethers.
• the amount of the solvent to be used is not particularly limited, but is preferably 1 to 150 times (v / w) with respect to the compound of the general formula [2e].
• Examples of the palladium catalyst used in this reaction include palladium metal such as palladium-carbon and palladium black; inorganic palladium salt such as palladium chloride; organic palladium salt such as palladium acetate; tetrakis (triphenylphosphine) palladium (0), Bis (triphenylphosphine) palladium (II) dichloride, 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) dichloride, tris (dibenzylideneacetone) dipalladium (0) and bis (di-tert-butyl ( Organic palladium complexes such as 4-dimethylaminophenyl) phosphine) palladium (II) dichloride; and polymer supported bis (acetate) triphenylphosphine palladium (II) and polymer supported di (acetate) dicyclohexyl Such as polymer-bound organic palladium complexe
• trialkylphosphines such as trimethylphosphine and tri-tert-butylphosphine
• tricycloalkylphosphines such as tricyclohexylphosphine
• triarylphosphine such as triphenylphosphine and tritolylphosphine.
• Reel phosphines such as trimethyl phosphite, triethyl phosphite and tributyl phosphite; tricycloalkyl phosphites such as tricyclohexyl phosphite; triaryl phosphites such as triphenyl phosphite; Imidazolium salts such as 3-bis (2,4,6-trimethylphenyl) imidazolium chloride; acetylacetone and octafluoroacetate Diketones such as luacetone; amines such as trimethylamine, triethylamine, tripropylamine and tributylamine; 1,1′-bis (diphenylphosphino) ferrocene; 2,2′-bis (diphenylphosphino) -1,1 ′ -Binaphthyl; 2-dicyclohexylphosphino-2 '
• Examples of the base used as desired in this reaction include inorganic bases such as sodium hydrogen carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate, and organic bases such as triethylamine and diisopropylethylamine.
• the amount of the base used may be 1 to 50 times mol, preferably 2 to 10 times mol, of the compound of the general formula [2e].
• the amount of the compound of the general formula [17a], [17b] or [17c] used may be 1 to 50 times mol, preferably 1 to 2 times mol for the compound of the general formula [2e].
• This reaction is usually carried out in an atmosphere of an inert gas (for example, nitrogen and / or argon) at 0 to 160 ° C., preferably 20 to 120 ° C., for 1 minute to 96 hours.
• an inert gas for example, nitrogen and / or argon
• the compound of the general formula [2i] can be produced by reacting the compound of the general formula [2h] with the compound of the general formula [4] according to the production method A.
• the compound of the general formula [2j] is prepared by reacting the compound of the general formula [2i] in the presence or absence of a base, in the presence of a palladium catalyst, in the presence or absence of a ligand according to the production method H-2. It can be produced by reacting with a compound of the general formula [17a], [17b] or [17c].
• R 1a is an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted C 1-12 alkyl group, or an optionally substituted C 2-12.
• An alkenyl group; R 2 , R 3 , R a , R e , R f and Z have the same meaning as described above.
• the compound of general formula [2m] is obtained by reacting the compound of general formula [3a] in the presence or absence of a base, in the presence of a palladium catalyst, in the presence or absence of a ligand. It can be produced by reacting with a compound of the general formula [18a], [18b] or [18c].
• a compound that can take the form of a salt can also be used as a salt.
• examples of such salts include the same salts as the salts of the compound of the general formula [1].
• the compound obtained by the above-described production method can be subjected to a reaction known per se such as condensation, addition, oxidation, reduction, rearrangement, substitution, halogenation, dehydration or hydrolysis, or the reaction can be appropriately performed. In combination, it can be derived into other compounds.
• the reaction when amino, hydroxyl and / or carboxyl groups are present, the reaction can be carried out by appropriately combining those protecting groups. Further, when there are two or more protecting groups, they can be selectively deprotected by subjecting them to a reaction known per se.
• formulation adjuvants such as excipients, carriers and diluents usually used for formulation may be appropriately mixed.
• excipients such as excipients, carriers and diluents usually used for formulation
• these are tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, powder formulations, suppositories, eye drops, nasal drops, ear drops, patches in accordance with conventional methods. It can be administered orally or parenterally in the form of an agent, ointment or injection.
• the administration method, the dosage, and the number of administrations can be appropriately selected according to the age, weight and symptoms of the patient. In general, for adults, oral administration or parenteral administration (for example, injection, infusion, administration to the rectal site, etc.), 0.01 to 1000 mg / kg can be divided into 1 to several times a day. Good.
• Test Example 1 Anti-HIV Activity Journal of Clinical Microbiology, 2007, Vol. 45, pp. 477-487. Anti-HIV activity was evaluated using MaRBLE cells into which human lymphocyte-derived HPB-M (a) was introduced with a luciferase gene whose expression was controlled by HIV-1 LTR, a CCR5 gene, and the like. A fresh medium or an appropriately diluted test compound was dispensed into a 96-well plate to prepare a drug solution-containing plate.
• MaRBLE cells were suspended in 10% FCS (fetal calf serum) and penicillin / streptomycin-containing RPMI1640, infected with HIV-1 (JRCSF), and then seeded (1 ⁇ 10 5 cells / well) on the above-mentioned drug solution plate .
• FCS fetal calf serum
• JRCSF penicillin / streptomycin-containing RPMI1640
• the same number of uninfected cells were seeded.
• intracellular luciferase activity was measured using Steady-Glo Luciferase assay system (Promega). The virus growth rate was determined by the following formula.
• Virus growth rate (%) (A / B) ⁇ 100
• A (fire fly luciferase activity in compound-added wells) ⁇ (non-infected cell fire fly luciferase activity)
• B (fire fly luciferase activity of compound-free well) ⁇ (uninfected cell fire fly luciferase activity)
• the IC 50 of the compound was calculated by plotting the concentration as a logarithm and the virus growth rate as a real number, and using the FORECAST function (primary regression method) of Microsoft Office Excel 2003. The results are shown in Table 1.
• the compound of the present invention had excellent anti-HIV activity.
• the mixing ratio in the eluent is a volume ratio.
• “eluent: 75-0% hexane / ethyl acetate” means that the eluent of 75% hexane / 25% ethyl acetate is finally changed to the eluent of 0% hexane / 100% ethyl acetate.
• the carrier in silica gel column chromatography is Fuji Silysia Chemical Ltd., silica gel, Purif-Pack SI (60 ⁇ m). In each example, each abbreviation has the following meaning.
• Reference example 1 A suspension of 1.00 g of ethyl 4-chloropyrimidine-5-carboxylate and 1.45 g of O-benzylhydroxylamine hydrochloride in 20 mL of N-ethyldiisopropylamine was heated and stirred at 110 to 120 ° C. for 3 hours. After cooling the reaction mixture, chloroform and water were added, and the organic layer was separated. The aqueous layer was extracted with chloroform, combined with the organic layer, dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [Yamazen Co., Ltd., Hi-Flash column, W001, eluent: 75-0% hexane / ethyl acetate] to give yellow oily substance ethyl 4-((benzyloxy) 1.06 g of amino) pyrimidine-5-carboxylate was obtained.
• the obtained residue was purified by silica gel column chromatography [Yamazen Co., Ltd., Hi-Flash column, W004, eluent: 80-0% hexane / ethyl acetate] to obtain 1.54 g of a yellow oil.
• 3.41 g of a 20% sodium ethoxide / ethanol solution was added dropwise to a solution of 1.54 g of the obtained yellow oil in 30 mL of ethanol, and the mixture was stirred at room temperature for 1 hour and 50 minutes.
• 2 mol / L hydrochloric acid was added to the reaction mixture to adjust to pH 2, and the mixture was stirred at room temperature for 30 minutes.
• the obtained residue was purified by silica gel column chromatography [eluent: 90-0% hexane / ethyl acetate], then suspended in a mixed solvent of 2-propanol and diisopropyl ether, and the precipitate was collected by filtration to give a white 35 mg of solid ethyl 8- (benzyloxy) -5-((2-naphthylmethyl) amino) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-6-carboxylate was obtained.
• the aqueous layer was extracted with chloroform, combined with the organic layer, dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [eluent: 99-85% chloroform / methanol], then suspended in a mixed solvent of 2-propanol and diisopropyl ether, and the precipitate was collected by filtration to give a brown solid 184 mg of 8- (benzyloxy) -5-(((pyridin-2-yl) methyl) amino) pyrido [2,3-d] pyrimidin-7 (8H) -one.
• reaction mixture is cooled and purified by silica gel column chromatography [eluent: 85-20% hexane / ethyl acetate], suspended in a mixed solvent of 2-propanol and diisopropyl ether, and the precipitate is collected by filtration.
• 68 mg of yellow solid ethyl 8- (benzyloxy) -5-((2,4-difluorobenzyl) amino) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-6-carboxylate Obtained.
• Reference Example 22 A suspension of 1.00 g of ethyl 4-chloro-2-methylpyrimidine-5-carboxylate and 1.35 g of O-benzylhydroxylamine hydrochloride in 16 mL of N-ethyldiisopropylamine was heated and stirred at 110 to 120 ° C. for 3 hours. After cooling the reaction mixture, chloroform and water were added, and the organic layer was separated. The aqueous layer was extracted with chloroform, combined with the organic layer, dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [eluent: 95-50% hexane / ethyl acetate] to obtain 2.56 g of a yellow oil.
• ethanol 15 mL
• 20% sodium ethoxide / ethanol solution (2.12 g) was added dropwise and stirred at room temperature for 4 hours.
• 2 mol / L hydrochloric acid was added to the reaction mixture to adjust to pH 3, and the mixture was stirred at room temperature for 10 minutes.
• the obtained residue was purified by silica gel column chromatography [eluent: 100-90% chloroform / methanol] to obtain 24 mg of a yellow solid.
• a yellow solid To 24 mg of the obtained yellow solid, 5 mL of methanol and 5 mL of a 1 mol / L aqueous sodium hydroxide solution were added, and the mixture was heated to reflux for 2 hours and 30 minutes. After cooling the reaction mixture, the solvent was distilled off under reduced pressure. 5 mL of water was added to the obtained residue, and the mixture was stirred at room temperature for 20 minutes.
• the solvent was distilled off from the reaction mixture under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [eluent: 95-60% hexane / ethyl acetate] to obtain a yellow oil (1.54 g).
• a solution of 1.54 g of the yellow oil obtained in 20 mL of ethanol 2.90 g of a 20% sodium ethoxide / ethanol solution was added dropwise and stirred at room temperature for 1 hour and 30 minutes. 2 mol / L hydrochloric acid was added to the reaction mixture to adjust to pH 3, and the mixture was stirred at room temperature for 10 minutes.
• Reference Example 44 A suspension of 517 mg of ethyl 4-chloro-6-methylpyrimidine-5-carboxylate and 699 mg of O-benzylhydroxylamine hydrochloride in 5 mL of N-ethyldiisopropylamine was heated and stirred at 110 to 120 ° C. for 1 hour and 30 minutes. After cooling the reaction mixture, chloroform and water were added, and the organic layer was separated. The aqueous layer was extracted with chloroform, combined with the organic layer, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
• reaction mixture was purified by silica gel column chromatography [eluent: 95-85% chloroform / methanol], then suspended in a mixed solvent of 2-propanol and diisopropyl ether, and the precipitate was collected by filtration to give a brown solid 8- 54 mg of (benzyloxy) -5- (morpholin-4-yl) pyrido [2,3-d] pyrimidin-7 (8H) -one was obtained.
• reaction mixture was purified by silica gel column chromatography [eluent: 65-0% hexane / ethyl acetate] to give 8- (benzyloxy) -5- (piperidin-1-yl) pyrido [2,3- d] 32 mg of pyrimidine-7 (8H) -one was obtained.
• the solvent was distilled off from the reaction mixture under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [eluent: 35-0% hexane / ethyl acetate] to obtain 177 mg of a brown oily substance.
• 9 mL of methanol and 9 mL of 1 mol / L aqueous sodium hydroxide solution were added, and the mixture was heated and stirred at 60 to 70 ° C. for 3 hours and 30 minutes. After cooling the reaction mixture, the solvent was distilled off under reduced pressure.
• the solvent was distilled off from the reaction mixture under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [eluent: 35-0% hexane / ethyl acetate] to obtain a brown oil (156 mg).
• a brown oil 156 mg
• 8 mL of methanol and 8 mL of 1 mol / L aqueous sodium hydroxide solution were added, and the mixture was heated with stirring at 60 to 70 ° C. for 4 hours and 30 minutes. After cooling the reaction mixture, the solvent was distilled off under reduced pressure.
• the solvent was distilled off from the reaction mixture under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [eluent: 70-0% hexane / ethyl acetate] to obtain 175 mg of a yellow oil.
• 8 mL of methanol and 8 mL of 1 mol / L sodium hydroxide aqueous solution were added, and the mixture was heated and stirred at 60 to 70 ° C. for 3 hours. After cooling the reaction mixture, the solvent was distilled off under reduced pressure.
• the solvent was distilled off from the reaction mixture under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [eluent: 70-0% hexane / ethyl acetate] to obtain 138 mg of a yellow oil.
• 6 mL of methanol and 6 mL of 1 mol / L sodium hydroxide aqueous solution were added, and the mixture was heated and stirred at 60 to 70 ° C. for 2 hours and 15 minutes. After cooling the reaction mixture, the solvent was distilled off under reduced pressure.
• the solvent was distilled off from the reaction mixture under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [eluent: 85-30% hexane / ethyl acetate] to obtain a yellow oil (139 mg).
• a yellow oil 139 mg
• 8 mL of methanol and 8 mL of 1 mol / L sodium hydroxide aqueous solution were added, and the mixture was heated and stirred at 70 to 80 ° C. for 3 hours. After cooling the reaction mixture, the solvent was distilled off under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [eluent: 70-0% hexane / ethyl acetate] to obtain a yellow oil (128 mg).
• a yellow oil (128 mg)
• 6 mL of methanol and 6 mL of 1 mol / L aqueous sodium hydroxide solution were added, and the mixture was heated and stirred at 60 to 70 ° C. for 2 hours and 45 minutes. After cooling the reaction mixture, the solvent was distilled off under reduced pressure.
• the solvent was distilled off from the reaction mixture under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [eluent: 70-0% hexane / ethyl acetate] to obtain a brown oil (125 mg).
• a brown oil 125 mg
• 5 mL of methanol and 5 mL of 1 mol / L aqueous sodium hydroxide solution were added, and the mixture was heated and stirred at 60 to 70 ° C. for 3 hours. After cooling the reaction mixture, the solvent was distilled off under reduced pressure.
• the solvent was distilled off from the reaction mixture under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [eluent: 60-0% hexane / ethyl acetate] to obtain a brown solid (160 mg).
• a brown solid 160 mg
• 10 mL of methanol and 10 mL of 1 mol / L sodium hydroxide aqueous solution were added, and the mixture was heated and stirred at 60 to 70 ° C. for 3 hours. After cooling the reaction mixture, the solvent was distilled off under reduced pressure, and ethyl acetate and water were added.
• the solvent was distilled off from the reaction mixture under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [eluent: 70-0% hexane / ethyl acetate] to obtain a white solid (200 mg).
• a white solid 200 mg
• 10 mL of methanol and 10 mL of 1 mol / L sodium hydroxide aqueous solution were added, and the mixture was heated and stirred at 60 to 70 ° C. for 2 hours and 30 minutes. After cooling the reaction mixture, the solvent was distilled off under reduced pressure, and ethyl acetate and water were added.
• the solvent was distilled off from the reaction mixture under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [eluent: 100-70% hexane / ethyl acetate] to obtain 48 mg of a pale yellow solid.
• 5 mL of methanol and 5 mL of a 1 mol / L aqueous sodium hydroxide solution were added, and the mixture was heated and stirred at 60 to 70 ° C. for 1 hour and 30 minutes and at 70 to 80 ° C. for 3 hours. After cooling the reaction mixture, the solvent was distilled off under reduced pressure.
• Reference Example 95 A suspension of 997 mg of ethyl 4-chloro-6-ethylpyrimidine-5-carboxylate and 1.25 g of O-benzylhydroxylamine hydrochloride in 10 mL of N-ethyldiisopropylamine was heated and stirred at 100 to 110 ° C. for 1 hour. After cooling the reaction mixture, chloroform and water were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [eluent: 70-30% hexane / ethyl acetate] to obtain 1.44 g of a yellow oil.
• silica gel column chromatography [eluent: 70-30% hexane / ethyl acetate] to obtain 1.44 g of a yellow oil.
• the obtained residue was purified by silica gel column chromatography [eluent: 100-85% chloroform / methanol] to obtain a yellow solid (32 mg).
• a yellow solid 32 mg
• 2 mL of 2 mol / L hydrochloric acid and 2 mL of dioxane were added, and the mixture was heated to reflux for 8 hours and 45 minutes.
• ethyl acetate and water were added.
• the organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
• Reference Example 104 0.33 mL of phosphorus oxychloride is added dropwise to a suspension of 17 mL of toluene of 830 mg of ethyl 4-benzyl-6-hydroxypyrimidine-5-carboxylate and 0.60 mL of N-ethyldiisopropylamine, and the mixture is heated and stirred at 70 to 80 ° C. for 1 hour. did. To the reaction mixture was added 10 mL of a 1 mol / L aqueous sodium hydroxide solution under ice cooling, and then ethyl acetate and water were added.
• Reference Example 105 A suspension of ethyl 4-benzyl-6-chloropyrimidine-5-carboxylate (755 mg) and O-benzylhydroxylamine hydrochloride (740 mg) in N-ethyldiisopropylamine (10 mL) was stirred with heating at 100 to 110 ° C. for 2 hours. After cooling the reaction mixture, chloroform and water were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [eluent: 75-0% hexane / ethyl acetate] to obtain 2.01 g of a brown oil.
• ethanol 26 mL
• 20% sodium ethoxide / ethanol solution 2.3 g
• 2 mol / L hydrochloric acid was added to the reaction mixture to adjust to pH 2, and the mixture was stirred at room temperature for 15 minutes and under ice-cooling for 15 minutes.
• the aqueous layer was separated and washed 4 times with ethyl acetate, 2 mol / L hydrochloric acid was added dropwise to adjust to pH 2, and ethyl acetate was added.
• the organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
• the organic layer was separated, washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, and then dried over sodium sulfate.
• the solvent was distilled off under reduced pressure to obtain 2.80 g of a brown oil.
• the obtained residue was purified by silica gel column chromatography [eluent: 85-30% hexane / ethyl acetate], suspended in a mixed solvent of 2-propanol and diisopropyl ether, and the precipitate was collected by filtration. 52 mg of 8- (benzyloxy) -5- (3,4-dihydroisoquinolin-2 (1H) -yl) pyrido [2,3-d] pyrimidin-7 (8H) -one as a yellow solid was obtained.
• reaction mixture was purified by silica gel column chromatography [eluent: 85-15% hexane / ethyl acetate] to give 8- (benzyloxy) -5-((1,2,3,4-tetrahydronaphthalene- 6 mg of 1-yl) amino) pyrido [2,3-d] pyrimidin-7 (8H) -one was obtained.
• the obtained residue was purified by silica gel column chromatography [eluent: 95-40% hexane / ethyl acetate] to obtain 4.40 g of a yellow oil.
• a solution of 4.40 g of the obtained yellow oil and 2.89 mL of triethylamine in 25 mL of methylene chloride was stirred at room temperature for 4 hours. Chloroform and water were added to the reaction mixture, 2 mol / L hydrochloric acid was added dropwise to adjust to pH 2, and the organic layer was separated. The aqueous layer was extracted with chloroform, combined with the organic layer, dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
• tert-butyl (3- (aminomethyl) phenyl) (methyl) carbamate 150 mg, triethylamine 88 ⁇ L and dioxane 10 mL were added, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off from the reaction mixture under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 80-50% hexane / ethyl acetate] to obtain a brown oil (222 mg).
• the solvent was distilled off from the reaction mixture under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [eluent: 100-95% chloroform / methanol] to obtain 79 mg of a brown oil.
• silica gel column chromatography [eluent: 100-95% chloroform / methanol] to obtain 79 mg of a brown oil.
• 7 mL of methanol and 7 mL of 1 mol / L aqueous sodium hydroxide solution were added, and the mixture was heated with stirring at 50 to 60 ° C. for 5 hours. After cooling the reaction mixture, the solvent was distilled off under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 80-20% hexane / ethyl acetate], and then suspended in 2-propanol. Filtration yielded 32 mg of 8- (benzyloxy) -5-((4-bromobenzyl) amino) pyrido [2,3-d] pyrimidin-7 (8H) -one as a brown solid.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 90-50% hexane / ethyl acetate] and then suspended in a mixed solvent of ethyl acetate and diisopropyl ether. The precipitate was collected by filtration, and 36 mg of 8- (benzyloxy) -5-((E) -2-phenylvinyl) pyrido [2,3-d] pyrimidin-7 (8H) -one as a pale yellow solid was collected. Obtained.
• the organic layer of the filtrate was separated, washed twice with a 10% aqueous citric acid solution, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 90-50% hexane / ethyl acetate], then suspended in diisopropyl ether, and the precipitate was filtered.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 80-20% hexane / ethyl acetate], and then suspended in a mixed solvent of 2-propanol and diisopropyl ether.
• the precipitate was collected by filtration and benzyl 4-(((8- (benzyloxy) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-5-yl) as a pale yellow solid) 12 mg of amino) methyl) benzoate were obtained.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 98-95% chloroform / methanol], and then mixed solvent of ethyl acetate, 2-propanol and diisopropyl ether
• the precipitate was collected by filtration to obtain 92 mg of an orange solid.
• 4.5 mL of methanol and 4.5 mL of 1 mol / L sodium hydroxide aqueous solution were added, and the mixture was heated and stirred at 60 to 70 ° C. for 2 hours, and then heated and stirred at 70 to 80 ° C. for 1 hour and 30 minutes.
• the aqueous layer was extracted with ethyl acetate, combined with the organic layer, washed successively with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-98% chloroform / methanol], suspended in diisopropyl ether, and the precipitate was collected by filtration. This gave 66 mg of yellow solid 8- (benzyloxy) -5-hydroxy-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-6-carboxamide.
• the reaction mixture was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform / methanol], and then purified by silica gel column chromatography [Kanto Chemical Co., Ltd., silica gel 60 (spherical). Eluent: 80-20% hexane / ethyl acetate], suspended in diisopropyl ether, and the precipitate was collected by filtration to give 5- (benzylamino) -8- (benzyloxy) -7 as a pale yellow solid.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 80-20% hexane / ethyl acetate], and then suspended in a mixed solvent of 2-propanol and diisopropyl ether.
• the precipitate was collected by filtration and collected as a pale yellow solid of 8- (benzyloxy) -5-((4- (methoxymethoxy) benzyl) amino) -4-methylpyrido [2,3-d] pyrimidine-7 ( 8 mg) -one 32 mg was obtained.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 80-20% hexane / ethyl acetate], and then suspended in a mixed solvent of 2-propanol and diisopropyl ether. The precipitate was collected by filtration, and a pale yellow solid of 8- (benzyloxy) -5-((2- (methoxymethoxy) benzyl) amino) -4-methylpyrido [2,3-d] pyrimidine-7 ( 8 mg) -one 21 mg was obtained.
• Reference Example 158 8- (Benzyloxy) -5-((2- (methoxymethoxy) benzyl) amino) -4-methylpyrido [2,3-d] pyrimidin-7 (8H) -one 20 mg in methanol 2.0 mL and dioxane 1.0 mL Was added with 15 ⁇ L of methanesulfonic acid and stirred at room temperature for 1 hour. To the reaction mixture, 60 ⁇ L of methanesulfonic acid was added and stirred at room temperature for 2 hours. To the reaction mixture, 45 ⁇ L of methanesulfonic acid was added and stirred at room temperature for 1 hour.
• Reference Example 160 8- (benzyloxy) -5-((3,4-bis (methoxymethoxy) benzyl) amino) -4-methylpyrido [2,3-d] pyrimidin-7 (8H) -one 23 mg of methanol 2.0 mL and dioxane To 1.0 mL suspension, 15 ⁇ L of methanesulfonic acid was added and stirred at room temperature for 1 hour. 15 ⁇ L of methanesulfonic acid was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours and 30 minutes. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 80-20% hexane / ethyl acetate], and then suspended in a mixed solvent of 2-propanol and diisopropyl ether. The precipitate was collected by filtration, and a pale yellow solid of 8- (benzyloxy) -5-((3- (methoxymethoxy) benzyl) amino) -4-methylpyrido [2,3-d] pyrimidine-7 ( 8 mg) -one 19 mg was obtained.
• reaction mixture was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 80-40% hexane / ethyl acetate], suspended in diisopropyl ether, and the precipitate was collected by filtration.
• a pale yellow solid of ethyl 5- (benzylamino) -8- (benzyloxy) -4-methoxy-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-6-carboxylate (36 mg) was obtained. .
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 90-30% hexane / ethyl acetate], and then suspended in a mixed solvent of 2-propanol and diisopropyl ether. The precipitate was collected by filtration to obtain 19 mg of 5- (benzylamino) -8- (benzyloxy) -6-iodopyrido [2,3-d] pyrimidin-7 (8H) -one as a yellow solid.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform / methanol], and white solid N- (2-(((8- 14 mg of (benzyloxy) -4-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-5-yl) amino) methyl) phenyl) -N- (methylsulfonyl) methanesulfonamide are obtained. It was.
• the solvent was distilled off from the reaction mixture under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-95% chloroform / methanol] to obtain 91 mg of a brown oil.
• silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-95% chloroform / methanol] to obtain 91 mg of a brown oil.
• 4.5 mL of methanol and 4.5 mL of a 1 mol / L aqueous sodium hydroxide solution were added, and the mixture was heated and stirred at 55-60 ° C. for 6 hours under a nitrogen atmosphere.
• saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added, and the organic layer was separated.
• the aqueous layer was extracted with ethyl acetate, combined with the organic layer, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 80-0% hexane / ethyl acetate-100-90% chloroform / methanol], ethyl acetate and The mixture was suspended in a mixed solvent of diisopropyl ether, and the precipitate was collected by filtration and collected as a yellow solid of 8- (benzyloxy) -4-methyl-5-(((quinolin-3-yl) methyl) amino) pyrido [2, 20 mg of 3-d] pyrimidin-7 (8H) -one was obtained.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform / methanol], then suspended in ethyl acetate, and the precipitate was collected by filtration. As a result, 40 mg of 8- (benzyloxy) -4-methyl-5-((3-nitrobenzyl) amino) pyrido [2,3-d] pyrimidin-7 (8H) -one as a pale yellow solid was obtained.
• Reference Example 180 8- (Benzyloxy) -4-methyl-5-((3-nitrobenzyl) amino) pyrido [2,3-d] pyrimidin-7 (8H) -one 25 mg of ethanol in a 1.2 mL suspension of water 0.18 mL, 2 mg of ammonium chloride and 10 mg of iron powder were added, and the mixture was heated to reflux for 1 hour. After cooling the reaction mixture, 1 mg of ammonium chloride and 5 mg of iron powder were added, and the mixture was heated to reflux for 30 minutes. After cooling the reaction mixture, chloroform and saturated aqueous sodium hydrogen carbonate solution were added, and the insoluble material was removed by filtration.
• the aqueous layer was extracted with ethyl acetate, combined with the organic layer, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 50-0% hexane / ethyl acetate-100-90% chloroform / methanol], ethyl acetate and Suspended in a mixed solvent of diisopropyl ether, the precipitate was collected by filtration, and 8 mg of 5-amino-8- (benzyloxy) -4-methylpyrido [2,3-d] pyrimidin-7 (8H) -one as a yellow solid Got.
• reaction mixture was added 2.0 mL of methylene chloride, 15 ⁇ L of triethylamine and 5 ⁇ L of benzoyl chloride, and the mixture was stirred at room temperature for 4 hours.
• 15 ⁇ L of triethylamine and 5 ⁇ L of benzoyl chloride were added, and the mixture was stirred at room temperature for 3 hours.
• the reaction mixture was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-93% chloroform / methanol], and then purified by silica gel column chromatography [Kanto Chemical Co., Ltd., silica gel 60 (spherical).
• the solvent was distilled off from the reaction mixture under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 80-30% hexane / ethyl acetate], and then silica gel column chromatography [Kanto Chemical Co., Ltd., silica gel 60 (spherical), eluent; chloroform] to obtain 144 mg of a yellow solid.
• ethanol 4.0 mL and 1 mol / L aqueous sodium hydroxide solution 4.0 mL were added. Under nitrogen atmosphere, 55-60 ° C. for 30 minutes, 60-65 ° C.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-95% chloroform / methanol] to obtain 83 mg of an orange solid.
• silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-95% chloroform / methanol] to obtain 83 mg of an orange solid.
• 3.0 mL of methanol and 3.0 mL of a 1 mol / L aqueous sodium hydroxide solution were added, and the mixture was heated and stirred at 60 to 65 ° C. for 2 hours and 30 minutes and at 65 to 70 ° C. for 2 hours in a nitrogen atmosphere.
• saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added, and the organic layer was separated.
• the aqueous layer was extracted with ethyl acetate, combined with the organic layer, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
• the obtained residue was suspended in ethyl acetate, and the precipitate was collected by filtration and collected as a pale yellow solid of 4-(((((8- (benzyloxy) -4-methyl-7-oxo-7,8-dihydropyrido [ 23 mg of 2,3-d] pyrimidin-5-yl) amino) methyl) benzenesulfonamide were obtained.
• the solvent was distilled off from the reaction mixture under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-96% chloroform / methanol] to obtain 54 mg of a brown oily substance.
• silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-96% chloroform / methanol] to obtain 54 mg of a brown oily substance.
• To 53 mg of the obtained brown oil 2.5 mL of methanol and 2.5 mL of a 1 mol / L aqueous sodium hydroxide solution were added, and the mixture was heated and stirred at 60 to 65 ° C. for 1 hour and at 65 to 70 ° C. for 4 hours in a nitrogen atmosphere. After cooling the reaction mixture, saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added.
• the solvent was distilled off from the reaction mixture under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 80-40% hexane / ethyl acetate] to obtain 125 mg of an orange oil.
• silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 80-40% hexane / ethyl acetate] to obtain 125 mg of an orange oil.
• 4.0 mL of methanol and 4.0 mL of a 1 mol / L aqueous sodium hydroxide solution were added, and the mixture was heated and stirred at 65 to 70 ° C. for 2 hours under a nitrogen atmosphere. After cooling the reaction mixture, saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added.
• the solvent was distilled off from the reaction mixture under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 80-0% hexane / ethyl acetate], and ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added. .
• the organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 232 mg of an orange oil.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 50-0% hexane / ethyl acetate-100-90% chloroform / methanol], ethyl acetate and The mixture was suspended in a mixed solvent of diisopropyl ether, and the precipitate was collected by filtration and collected as a pale yellow solid of 8- (benzyloxy) -5-(((isoquinolin-4-yl) methyl) amino) -4-methylpyrido [2, 33 mg of 3-d] pyrimidin-7 (8H) -one was obtained.
• the aqueous layer was extracted with chloroform, combined with the organic layer, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 205 mg of a yellow oil.
• 4.0 mL of methanol and 4.0 mL of a 1 mol / L aqueous sodium hydroxide solution were added, and the mixture was heated with stirring at 60 to 65 ° C. for 8 hours under a nitrogen atmosphere. After cooling the reaction mixture, water and chloroform were added, and the organic layer was separated. The aqueous layer was extracted with chloroform, combined with the organic layer, dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
• Reference Example 202 8- (benzyloxy) -5-((4-hydroxybenzyl) amino) -4-methylpyrido [2,3-d] pyrimidin-7 (8H) -one in 64 mg of DMF in 1.3 mL was added to 114 mg of potassium carbonate and 2 -Add 35 ⁇ L of bromoethanol and stir at 70-80 ° C. for 2 hours. After cooling the reaction mixture, 114 mg of potassium carbonate and 35 ⁇ L of 2-bromoethanol were added, and the mixture was heated with stirring at 70-80 ° C. for 3 hours. After cooling the reaction mixture, potassium carbonate (114 mg) and 2-bromoethanol (35 ⁇ L) were added, and the mixture was heated with stirring at 80 to 85 ° C.
• the solvent was distilled off from the reaction mixture under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 80-20% hexane / ethyl acetate] to obtain 267 mg of a yellow oily substance.
• Methanol (5.0 mL) and 1 mol / L aqueous sodium hydroxide solution (5.0 mL) were added to the obtained yellow oil (266 mg), and the mixture was heated with stirring at 55 to 60 ° C. for 6 hours under a nitrogen atmosphere.
• the solvent was distilled off from the reaction mixture under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform / methanol], then suspended in diisopropyl ether and the precipitate collected by filtration.
• An orange solid 63 mg was obtained.
• To 60 mg of the obtained orange solid 3.0 mL of methanol and 3.0 mL of a 1 mol / L aqueous sodium hydroxide solution were added and heated to reflux for 2 hours. After cooling the reaction mixture, 1 mol / L hydrochloric acid was added dropwise to adjust the pH to 7. Ethyl acetate was added to the reaction mixture.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 60-0% hexane / ethyl acetate] and suspended in a mixed solvent of diisopropyl ether and ethyl acetate. The precipitate was collected by filtration to obtain 77 mg of a pale yellow solid. To 75 mg of the obtained pale yellow solid, 3.0 mL of methanol and 3.0 mL of 1 mol / L sodium hydroxide aqueous solution were added and heated under reflux for 1 hour.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 70-30% hexane / ethyl acetate], suspended in diisopropyl ether, and the precipitate was collected by filtration. To obtain 92 mg of a yellow solid. To 90 mg of the obtained yellow solid, 3.0 mL of methanol and 3.0 mL of 1 mol / L sodium hydroxide aqueous solution were added, and the mixture was heated and stirred at 70 ° C. for 2 hours.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 50-30% hexane / ethyl acetate], suspended in diisopropyl ether and the precipitate collected by filtration. As a result, 81 mg of a yellowish red solid was obtained. To 78 mg of the obtained yellow-red solid, 3.0 mL of methanol and 3.0 mL of a 1 mol / L sodium hydroxide aqueous solution were added, and the mixture was heated and stirred at 70 ° C. for 2 hours.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 40-20% hexane / ethyl acetate] to obtain a brown oil.
• silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 40-20% hexane / ethyl acetate] to obtain a brown oil.
• 3.0 mL of methanol and 3.0 mL of 1 mol / L sodium hydroxide aqueous solution were added, and the mixture was heated and stirred at 70 ° C. for 4 hours.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-90% chloroform / methanol] to obtain 404 mg of a brown oily substance.
• silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-90% chloroform / methanol] to obtain 404 mg of a brown oily substance.
• 3.0 mL of methanol and 3.0 mL of 1 mol / L aqueous sodium hydroxide solution were added, and the mixture was heated with stirring at 70 ° C. for 3 hours.
• ethyl acetate was added, 1 mol / L hydrochloric acid was added dropwise to adjust to pH 7, and the organic layer was separated.
• the aqueous layer was extracted with ethyl acetate, combined with the organic layer, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 60-20% hexane / ethyl acetate], suspended in diisopropyl ether, and the precipitate was filtered.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-85% chloroform / methanol] to obtain 373 mg of a brown oily substance.
• methanol 3.0 mL
• a 1 mol / L aqueous sodium hydroxide solution 3.0 mL
• ethyl acetate was added, 1 mol / L hydrochloric acid was added dropwise to adjust to pH 7, and the organic layer was separated.
• the aqueous layer was extracted with ethyl acetate, combined with the organic layer, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
• the obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd. DNH silica, eluent: 50-10% hexane / ethyl acetate], suspended in diisopropyl ether, and the precipitate was collected by filtration.
• the reaction mixture was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 60-20% hexane / ethyl acetate] to obtain 296 mg of a brown oil.
• methanol 6.0 mL
• a 1 mol / L aqueous sodium hydroxide solution 6.0 mL
• 6 mol / L hydrochloric acid was added dropwise to adjust the pH to 7.
• the reaction mixture was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 60-20% hexane / ethyl acetate] to obtain 259 mg of a brown oil.
• methanol 6.0 mL
• a 1 mol / L aqueous sodium hydroxide solution 6.0 mL
• 6 mol / L hydrochloric acid was added dropwise to adjust to pH 7, butanol was added, and the solvent was distilled off under reduced pressure.
• the reaction mixture was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 70-30% hexane / ethyl acetate] to obtain 240 mg of a brown oil.
• silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 70-30% hexane / ethyl acetate] to obtain 240 mg of a brown oil.
• 6.0 mL of methanol and 6.0 mL of 1 mol / L sodium hydroxide aqueous solution were added, and the mixture was heated and stirred at 60 ° C. for 3 hours. After cooling the reaction mixture, 6 mol / L hydrochloric acid was added dropwise to adjust the pH to 7.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 70-30% hexane / ethyl acetate] to obtain 293 mg of a brown oily substance.
• methanol 6.0 mL
• a 1 mol / L aqueous sodium hydroxide solution 6.0 mL
• 6 mol / L hydrochloric acid was added dropwise to adjust the pH to 7.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 70-0% hexane / ethyl acetate], suspended in diisopropyl ether, and the precipitate was filtered. Taking 181 mg of a brown solid. To 174 mg of the obtained brown solid, 3.0 mL of methanol and 3.0 mL of 1 mol / L sodium hydroxide aqueous solution were added, and the mixture was heated and stirred at 60 ° C. for 4 hours.
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 50-30% hexane / ethyl acetate] to obtain 148 mg of a brown oil.
• silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 50-30% hexane / ethyl acetate] to obtain 148 mg of a brown oil.
• methanol 3.0 mL
• a 1 mol / L aqueous sodium hydroxide solution 3.0 mL
• the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 50-20% hexane / ethyl acetate] to obtain 207 mg of a pale yellow oil.
• Methanol (3.0 mL) and a 1 mol / L aqueous sodium hydroxide solution (3.0 mL) were added to the obtained pale yellow oil (207 mg), and the mixture was heated to reflux for 4 hours. After cooling the reaction mixture, 6 mol / L hydrochloric acid was added dropwise to adjust to pH 8, and the solvent was distilled off under reduced pressure. Butanol was added to the obtained residue, and the solvent was distilled off under reduced pressure.
• Example 1 To 138 mg of 8- (benzyloxy) -5-((4-methoxybenzyl) amino) pyrido [2,3-d] pyrimidin-7 (8H) -one, 69 mg of 10% palladium-carbon and 25 mL of methanol were added, and hydrogen was added. The mixture was stirred at room temperature for 1 hour and 10 minutes. Palladium-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.
• Example 2 To 13 mg of 5- (benzylamino) -8- (benzyloxy) pyrido [2,3-d] pyrimidin-7 (8H) -one was added 7 mg of 10% palladium-carbon and 7 mL of methanol, and at room temperature under a hydrogen atmosphere. Stir for 5 minutes. Palladium-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure. The obtained residue was suspended in a mixed solvent of 2-propanol and diisopropyl ether, and the precipitate was collected by filtration to give 5- (benzylamino) -8-hydroxypyrido [2,3-d] pyrimidine as a white solid.
• Example 3 To 17 mg of 8- (benzyloxy) -5-((2-naphthylmethyl) amino) pyrido [2,3-d] pyrimidin-7 (8H) -one, 8 mg of 10% palladium-carbon and 8 mL of methanol were added, and hydrogen was added. Stir for 15 minutes at room temperature under atmosphere. Ethanol (5 mL) was added, and the mixture was stirred at room temperature for 10 minutes in a hydrogen atmosphere. Palladium-carbon was filtered off and washed with ethanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.
• Example 4 8- (benzyloxy) -7-oxo-5-(((trifluoromethyl) sulfonyl) oxy) -7,8-dihydropyrido [2,3-d] pyrimidine-6-carboxylate 90 mg and aminomethylcyclohexane 99 ⁇ L of dioxane 9 mL solution was heated and stirred at 90-100 ° C. for 2 hours 30 minutes. After cooling the reaction mixture, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-50% hexane / ethyl acetate] to obtain 329 mg of a yellow oil.
• Example 5 8- (benzyloxy) -5-((((pyridin-2-yl) methyl) amino) pyrido [2,3-d] pyrimidin-7 (8H) -one to 176 mg, 10% palladium-carbon 88 mg and methanol 35 mL And stirred at room temperature for 1 hour and 30 minutes in a hydrogen atmosphere. Palladium-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.
• Example 6 To 24 mg of 8- (benzyloxy) -5-((2,4-difluorobenzyl) amino) pyrido [2,3-d] pyrimidin-7 (8H) -one, 12 mg of 10% palladium-carbon and 10 mL of methanol were added. The mixture was stirred at room temperature for 10 minutes under a hydrogen atmosphere. Palladium-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.
• Example 7 To 9 mg of 8- (benzyloxy) -5-((1-phenylethyl) amino) pyrido [2,3-d] pyrimidin-7 (8H) -one, 5 mg of 10% palladium-carbon and 8 mL of methanol were added, and hydrogen was added. Stir for 15 minutes at room temperature under atmosphere. Palladium-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.
• Example 8 To 28 mg of 8- (benzyloxy) -5- (cyclohexylamino) pyrido [2,3-d] pyrimidin-7 (8H) -one was added 14 mg of 10% palladium-carbon and 10 mL of methanol, and at room temperature under a hydrogen atmosphere. Stir for 10 minutes. Palladium-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.
• Example 9 8- (Benzyloxy) -5-((2,3-dihydro-1H-inden-1-yl) amino) pyrido [2,3-d] pyrimidin-7 (8H) -one in 75 mg, 10% palladium- 38 mg of carbon and 18 mL of methanol were added, and the mixture was stirred at room temperature for 20 minutes under a hydrogen atmosphere. Palladium-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.
• Example 10 8- (benzyloxy) -5-((2,3-dihydro-1H-inden-2-yl) amino) pyrido [2,3-d] pyrimidin-7 (8H) -one in 36 mg, 10% palladium- 18 mg of carbon and 20 mL of methanol were added, and the mixture was stirred at room temperature for 30 minutes in a hydrogen atmosphere. Palladium-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.
• Example 11 Ethyl 8- (benzyloxy) -5-((4-methoxybenzyl) amino) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-6-carboxylate 30 mg in a 10 mL ethanol solution 10% palladium-carbon (15 mg) was added, and the mixture was stirred at room temperature for 2 hours and 5 minutes in a hydrogen atmosphere. Palladium-carbon was filtered off and washed with ethanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure. The obtained residue was suspended in a mixed solvent of methanol and diisopropyl ether, and the solid was collected by filtration.
• Example 12 8- (Benzyloxy) -5-((4-methoxybenzyl) amino) -2-methylpyrido [2,3-d] pyrimidin-7 (8H) -one (64 mg), 10% palladium-carbon (32 mg) and methanol (13 mL) In addition, the mixture was stirred at room temperature for 30 minutes under a hydrogen atmosphere. Palladium-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.
• Example 13 8- (benzyloxy) -2-hydroxy-5-((4-methoxybenzyl) amino) pyrido [2,3-d] pyrimidin-7 (8H) -one in 50 mg, 25% 10% palladium-carbon and 38 mL ethanol And stirred for 30 minutes at room temperature under hydrogen atmosphere. Palladium-carbon was filtered off and washed with ethanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.
• Example 14 2-Amino-8- (benzyloxy) -5-((4-methoxybenzyl) amino) pyrido [2,3-d] pyrimidin-7 (8H) -one in 16 mg, 10% palladium-carbon 8 mg and methanol 10 mL And stirred for 30 minutes at room temperature under hydrogen atmosphere. Palladium-carbon was filtered off and washed with methanol, ethanol and chloroform. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.
• Example 15 Ethyl 8- (benzyloxy) -5-hydroxy-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-6-carboxylate (150 mg) was mixed with 8 mL of methanol and 8 mL of a 1 mol / L aqueous sodium hydroxide solution. In addition, the mixture was heated to reflux for 5 hours. After cooling the reaction mixture, the solvent was distilled off under reduced pressure. To the obtained residue, 5 mL of a 1 mol / L aqueous sodium hydroxide solution was added, concentrated hydrochloric acid was added dropwise to adjust to pH 1, and the mixture was stirred at room temperature for 20 minutes.
• Example 16 To 10 mg of 5-anilino-8- (benzyloxy) pyrido [2,3-d] pyrimidin-7 (8H) -one, add 5 mg of 10% palladium-carbon, 4 mL of ethyl acetate and 4 mL of methanol. For 20 minutes. Palladium-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure. The obtained residue was suspended in a mixed solvent of 2-propanol and diisopropyl ether, and the precipitate was collected by filtration to give 5-anilino-8-hydroxypyrido [2,3-d] pyrimidine-7 as a pale green solid.
• Example 17 To 43 mg of 8- (benzyloxy) -5-((2-phenylethyl) amino) pyrido [2,3-d] pyrimidin-7 (8H) -one, 22 mg of 10% palladium-carbon and 15 mL of methanol were added, and hydrogen was added. The mixture was stirred at room temperature for 1 hour and 20 minutes. Palladium-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.
• Example 18 To 20 mg of 8- (benzyloxy) -5-((pyridin-3-ylmethyl) amino) pyrido [2,3-d] pyrimidin-7 (8H) -one, 10 mg of 10% palladium-carbon and 10 mL of methanol were added. The mixture was stirred at room temperature for 1 hour and 35 minutes in a hydrogen atmosphere. Palladium-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.
• Example 19 To 53 mg of 5- (benzyl (methyl) amino) -8- (benzyloxy) pyrido [2,3-d] pyrimidin-7 (8H) -one was added 27 mg of 10% palladium-carbon and 12 mL of methanol, and in a hydrogen atmosphere. And stirred at room temperature for 25 minutes. Palladium-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure. The obtained residue was suspended in a mixed solvent of methanol and diisopropyl ether, and the precipitate was collected by filtration to give 5- (benzyl (methyl) amino) -8-hydroxypyrido [2,3-d as a light brown solid.
• Example 20 5- (benzylamino) -8- (benzyloxy) -2- (trifluoromethyl) pyrido [2,3-d] pyrimidin-7 (8H) -one (31 mg), 10% palladium-carbon (16 mg) and methanol (12 mL) In addition, the mixture was stirred for 15 minutes at room temperature in a hydrogen atmosphere. Palladium-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.
• Example 21 To 38 mg of 8- (benzyloxy) -5-hydroxy-4-methylpyrido [2,3-d] pyrimidin-7 (8H) -one, 19 mg of 10% palladium-carbon and 20 mL of methanol were added, and at room temperature under a hydrogen atmosphere. Stir for 7 minutes. Palladium-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure. The obtained residue was suspended in a mixed solvent of 2-propanol and diisopropyl ether, and the precipitate was collected by filtration to give 5,8-dihydroxy-4-methylpyrido [2,3-d] pyrimidine-7 as a yellow-green solid. 12 mg of (8H) -one was obtained. 1 H-NMR (DMSO-d 6 ) ⁇ value: 2.85 (s, 3H), 5.91 (s, 1H), 8.85 (s, 1H), 10.83 (brs, 1H).
• Example 22 To 52 mg of 5- (benzylamino) -8- (benzyloxy) -4-methylpyrido [2,3-d] pyrimidin-7 (8H) -one, 26 mg of 10% palladium-carbon and 20 mL of methanol were added, and hydrogen atmosphere was added. And stirred for 8 minutes at room temperature. Palladium-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.
• Example 23 To 50 mg of 8- (benzyloxy) -5-hydroxy-6-phenylpyrido [2,3-d] pyrimidin-7 (8H) -one, 25 mg of 10% palladium-carbon and 30 mL of methanol were added, and at room temperature under a hydrogen atmosphere. Stir for 7 minutes. Palladium-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure. The obtained residue was suspended in a mixed solvent of 2-propanol and diisopropyl ether, the solid was collected by filtration, and 5,8-dihydroxy-6-phenylpyrido [2,3-d] pyrimidine-7 as a pale yellow green solid was collected.
• Example 24 To 30 mg of 8- (benzyloxy) -5-hydroxy-6-methylpyrido [2,3-d] pyrimidin-7 (8H) -one was added 15 mg of 10% palladium-carbon and 20 mL of methanol, and at room temperature under a hydrogen atmosphere. Stir for 7 minutes. Palladium-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure. The obtained residue was suspended in a mixed solvent of 2-propanol and diisopropyl ether, the precipitate was collected by filtration, and gray solid of 5,8-dihydroxy-6-methylpyrido [2,3-d] pyrimidine-7 ( 10 mg of 8H) -one was obtained.
• Example 25 To 54 mg of 8- (benzyloxy) -5- (morpholin-4-yl) pyrido [2,3-d] pyrimidin-7 (8H) -one, 27 mg of 10% palladium-carbon and 20 mL of methanol were added, and hydrogen atmosphere was added. And stirred for 11 minutes at room temperature. Palladium-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure. The obtained residue was suspended in a mixed solvent of 2-propanol and diisopropyl ether, and the precipitate was collected by filtration to give 8-hydroxy-5- (morpholin-4-yl) pyrido [2,3-d as a brown solid.
• Example 26 To 7 mg of 8- (benzyloxy) -5- (piperidin-1-yl) pyrido [2,3-d] pyrimidin-7 (8H) -one, 7 mg of 10% palladium-carbon and 20 mL of methanol were added, and hydrogen atmosphere was added. And stirred at room temperature for 20 minutes. Palladium-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined, the solvent was distilled off under reduced pressure, and 3 mg of 8-hydroxy-5- (piperidin-1-yl) pyrido [2,3-d] pyrimidin-7 (8H) -one as a brown solid was obtained. Obtained.
• Example 27 To 21 mg of 1- (benzyloxy) -4-hydroxypyrimido [4,5-d] pyrimidin-2 (1H) -one was added 11 mg of 10% palladium-carbon, 3.2 mL of ethanol and 3.2 mL of ethyl acetate, and a hydrogen atmosphere The mixture was stirred at room temperature for 1 hour and 30 minutes. Palladium-carbon was filtered off and washed with a mixed solvent of ethyl acetate and dioxane. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.
• Example 28 8- (benzyloxy) -4-methyl-5-((3- (trifluoromethyl) benzyl) amino) pyrido [2,3-d] pyrimidin-7 (8H) -one in 20 mg, 20% palladium hydroxide -10 mg of carbon and 20 mL of methanol were added and stirred for 10 minutes at room temperature under hydrogen atmosphere. Palladium hydroxide-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.
• Example 29 8- (benzyloxy) -5-((3- (dimethylamino) benzyl) amino) -4-methylpyrido [2,3-d] pyrimidin-7 (8H) -one in 20 mg, 20% palladium hydroxide-carbon 10 mg, 16 mL of methanol and 8 mL of dioxane were added, and the mixture was stirred at room temperature for 10 minutes under a hydrogen atmosphere. Palladium hydroxide-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.
• Example 30 8- (benzyloxy) -5-((4- (dimethylamino) benzyl) amino) -4-methylpyrido [2,3-d] pyrimidin-7 (8H) -one in 20 mg, 20% palladium hydroxide-carbon 10 mg, 50 mL of methanol and 25 mL of dioxane were added, and the mixture was stirred at room temperature for 10 minutes under a hydrogen atmosphere. Palladium hydroxide-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.
• Example 31 8- (benzyloxy) -5-((3-methoxybenzyl) amino) -4-methylpyrido [2,3-d] pyrimidin-7 (8H) -one 40 mg, 20% palladium hydroxide-carbon 20 mg, methanol 25 mL was added, and the mixture was stirred at room temperature for 7 minutes under a hydrogen atmosphere. Palladium hydroxide-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.
• Example 32 8- (benzyloxy) -5-((4-methoxybenzyl) amino) -4-methylpyrido [2,3-d] pyrimidin-7 (8H) -one 52 mg, 20% palladium hydroxide-carbon 26 mg, methanol 25 mL was added, and the mixture was stirred at room temperature for 7 minutes under a hydrogen atmosphere. Palladium hydroxide-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.
• Example 33 8- (benzyloxy) -5-((2-methoxybenzyl) amino) -4-methylpyrido [2,3-d] pyrimidin-7 (8H) -one 40 mg, 20% palladium hydroxide-carbon 20 mg and methanol 25 mL was added, and the mixture was stirred at room temperature for 7 minutes under a hydrogen atmosphere. Palladium hydroxide-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.
• Example 34 3-(((8- (Benzyloxy) -4-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-5-yl) amino) methyl) benzonitrile (11 mg) with 20% water Palladium oxide-carbon 6 mg, methanol 10 mL, and dioxane 5 mL were added, and the mixture was stirred at room temperature for 5 minutes in a hydrogen atmosphere. Palladium hydroxide-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.
• Example 35 8- (benzyloxy) -5-((cyclohexylmethyl) amino) -4-methylpyrido [2,3-d] pyrimidin-7 (8H) -one in 40 mg, 20% palladium hydroxide-carbon 20 mg, methanol 20 mL and Dioxane (10 mL) was added, and the mixture was stirred at room temperature for 7 minutes in a hydrogen atmosphere. Palladium hydroxide-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.
• Example 36 8- (benzyloxy) -5-((2-fluorobenzyl) amino) -4-methylpyrido [2,3-d] pyrimidin-7 (8H) -one 48 mg, 20% palladium hydroxide-carbon 24 mg, methanol 20 mL and 10 mL of dioxane were added, and the mixture was stirred at room temperature for 5 minutes in a hydrogen atmosphere. Palladium hydroxide-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.
• Example 37 8- (benzyloxy) -5- (cyclohexylamino) -4-methylpyrido [2,3-d] pyrimidin-7 (8H) -one 28 mg, 20% palladium hydroxide-carbon 14 mg, methanol 20 mL and dioxane 10 mL In addition, the mixture was stirred for 3 minutes at room temperature in a hydrogen atmosphere. Palladium hydroxide-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.
• Example 38 8- (benzyloxy) -5-((2,4-dimethoxybenzyl) amino) -4-methylpyrido [2,3-d] pyrimidin-7 (8H) -one (26 mg), 20% palladium hydroxide-carbon (13 mg) , 20 mL of methanol and 10 mL of dioxane were added, and the mixture was stirred at room temperature for 6 minutes in a hydrogen atmosphere. Palladium hydroxide-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.
• Example 39 8- (benzyloxy) -5-((4- (diethylamino) benzyl) amino) -4-methylpyrido [2,3-d] pyrimidin-7 (8H) -one 35 mg, 20% palladium hydroxide-carbon 17 mg , 20 mL of methanol and 10 mL of dioxane were added, and the mixture was stirred at room temperature for 5 minutes in a hydrogen atmosphere. Palladium hydroxide-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.
• Example 40 To 56 mg of 8- (benzyloxy) -5-(((6- (dimethylamino) pyridin-3-yl) methyl) amino) -4-methylpyrido [2,3-d] pyrimidin-7 (8H) -one, 20% palladium hydroxide-carbon (28 mg), methanol (20 mL) and dioxane (10 mL) were added, and the mixture was stirred at room temperature for 5 minutes in a hydrogen atmosphere. Palladium hydroxide-carbon was removed by filtration and washed with methanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure.

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